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Neuroscience Letters 496 (2011) 90–94

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Differential expression of FosB, c-Fos, and Zif268 in forebrain regions after acuteor chronic l-DOPA treatment in a rat model of Parkinson’s disease
Kosuke Ebihara a , Yasushi Ishida a,∗ , Ryuichiro Takeda a , Hiroshi Abe a , Hisae Matsuo a , Keiichi Kawai b ,Yasuhiro Magata c , Toshikazu Nishimori daDepartment of Psychiatry, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan
Department of Quantum Medical Technology, Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kodatsuno,
Kanazawa 920-0942, Japanc
Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japand
Division of Neurobiology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japanba r t i c l e

i n f oArticle history:
Received 18 November 2010
Received in revised form 17 February 2011
Accepted 30 March 2011
Keywords:
6-Hydroxydopaminel-DOPA
Abnormal involuntary movement
Immediate-early gene protein
Immunohistochemistrya b s t r a c t
A study was carried out to examine the effects of acute and chronic l-DOPA treatment on the distributionof the immediate-early gene (IEG) proteins (FosB, c-Fos, and Zif268) in forebrain regions in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease. During a course of chronic l-DOPA
treatment (15 mg/day, 15 days), rats with a 6-OHDA lesion developed abnormal involuntary movements.
Compared with the rats in the acute l-DOPA treatment group, those in the chronic treatment group had
signiﬁcantly more FosB-immunopositive cells in the anterior cingulate (Cg) and the dorsolateral caudateputamen ipsilateral to the lesion and signiﬁcantly fewer c-Fos-immunopositive cells in the Cg, the nucleus
accumbens shell, and the basolateral nucleus of amygdala ipsilateral to the lesion. No signiﬁcant difference was observed in the number of Zif268-immunopositive cells between the acute and chronic l-DOPA
groups. In summary, differential expression of three IEG proteins was observed in the forebrain regions
during a course of chronic l-DOPA treatment of 6-OHDA-treated hemiparkinsonian rats.
© 2011 Elsevier Ireland Ltd. All rights reserved.

Pharmacological dopamine (DA) replacement therapy using lDOPA remains the most effective treatment for Parkinson’s disease(PD). However, long-term l-DOPA treatment of patients with PD
often induces not only motor complications such as ﬂuctuationand dyskinesia but also psychotic conditions such as hallucinations,
delusions, and impulse control problems [14,24]. The mechanisms
underlying the l-DOPA-induced motor complications have been
investigated in a number of neuropharmacological studies [7].
However, few studies have investigated the mechanisms underlying the l-DOPA-induced psychotic conditions.
Induction of cellular immediate-early genes (IEGs) may be a
critical signal transduction step in neuronal plasticity induced byneurotransmitters and drugs, with the protein products of the IEGs
functioning to either activate or repress genes that encode the proteins involved in the differentiated functions of the target neurons.
This study examined the distribution of the IEG proteins (FosB, cFos, and Zif268) after acute and after chronic l-DOPA treatmentin the forebrain regions including the striatal and limbic structures(anterior cingulate (Cg), nucleus accumbens shell (AcbSh), caudateputamen (CPu), and basolateral nucleus of amygdala (BLA)) in a

∗ Corresponding author. Tel.: +81 985 85 2969; fax: +81 985 85 5475.
E-mail address: ishiday@med.miyazaki-u.ac.jp (Y. Ishida).
0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2011.03.087

unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s
disease.
The 6-OHDA lesioned rat model of Parkinson’s disease has been
instrumental in studies using a variety of approaches to investigate
l-DOPA-induced plasticity at multiple levels. Among the postsynaptic changes examined, the striatal expression of prodynorphin(preproenkephalin-B) mRNA and FosB/FosB-like transcription
factors has shown a particularly strong positive correlation with theseverity of l-DOPA-induced dyskinesia [2,6,25]. Cenci found that
acute injection of l-DOPA increased the levels of FosB and c-Fos in
the 6-OHDA-lesioned striatum, whereas repeated administrationof the drug caused downregulation of c-Fos and upregulation of
FosB [5,8]. Carta et al. found that zif268 mRNA levels increased in
the 6-OHDA-lesioned striatum after either acute or subchronic lDOPA treatment [4]. However, there have been few investigationsof the l-DOPA-induced IEG proteins in the brain structures otherthan the striatum [10].
The study reported here examined the effects of acute andchronic l-DOPA treatment on the distribution of the IEG proteins inforebrain regions in a unilateral 6-OHDA rat model of Parkinson’s
disease. The experimental protocols used were approved by the
ethical committees of animal experimentation at the University ofMiyazaki. Anesthetized male 120–130 g Wistar rats (Charles River,Japan) received stereotaxic injections of 8-␮g 6-OHDA hydrobro-

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K. Ebihara et al. / Neuroscience Letters 496 (2011) 90–94

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Fig. 1. Effect of chronic l-DOPA treatment on AIMs. Four subtypes of AIMs (locomotive (A), axial (B), forelimb (C), and orolingual (D)) were scored on the 1st and 14th daysof l-DOPA administration for the chronic l-DOPA treated rats (n = 8). Data represent the mean (±SEM) AIM score for ﬁrst 60 min after l-DOPA administration. Each scoreshowed a signiﬁcant increase on the 14th day compared to that on the 1st day of l-DOPA administration (*P < 0.05, Wilcoxon signed rank test).

mide (Sigma, MA, USA) in 4 ␮l of sterile saline containing 0.01%
ascorbic acid. The stereotaxic coordinates for the lesion were
3.2 mm rostral to the interaural line, 1.3 mm left of the midline, and6.7 mm ventral to the dural surface. The incisor bar was set 2.4 mm
below the level of the ear bars [20]. The injections of 6-OHDA immediately and almost completely destroyed the DA neurons of thesubstantia nigra and of the ventral tegmental area, resulting in thenear total depletion (2% of normal) of DA in the ipsilateral striatum[16].
Two weeks later, motor disturbance was assessed by counting
the full rotations per min in a cylindrical container (30-cm diameter) at 10-min intervals for the ﬁrst 60 min after methamphetamine(3 mg/kg, i.p.) administration. The animals that turned no less thanseven times/min were included in the study.
The rats that were included were allocated into threewell-matched groups (in accordance with the methamphetamineinduced rotation): (1) chronic l-DOPA treatment (n = 9), (2) acutel-DOPA treatment (n = 7), and (3) saline treatment (n = 8). Those in
the ﬁrst group received a daily injection of l-DOPA methyl esterhydrochloride (15 mg/kg, i.p.; Sigma, MA, USA) plus an injectionof benserazide hydrochloride (15 mg/kg, i.p.; Sigma) for 15 days.
Those in the second group received a daily injection of an equivalent
volume of saline (i.p.) for 14 days and then an injection of l-DOPAplus benserazide on the 15th day. Those in the third received a daily
injection of an equivalent volume of saline for 15 days. This pattern of l-DOPA administration was based on previous ﬁndings thatcircling is signiﬁcantly enhanced after 7 or 8 daily injections of lDOPA (13 mg/kg, i.p.) and that this potentiated behavioral response
reaches a plateau by day 14 [15]. This enhanced response is thought
to be a useful model for the l-DOPA-induced dyskinesia seen inhuman patients with PD [15].
The l-DOPA-induced abnormal involuntary movements (AIMs)of the rats in the chronic treatment group were scored on the
1st and 14th days in accordance with a rat dyskinesia scale [6]with modiﬁcation. The rats were observed at 10-min intervals forthe ﬁrst 60 min after l-DOPA administration (6 monitoring periods of 1 min each). The AIMs were classiﬁed into four subtypes:
locomotive (increased locomotion towards the side contralateral
to the lesion), axial (dystonic posturing or choreiform twisting of

the neck and upper body towards the contralateral side), forelimb(abnormal, purposeless movements of the forelimbs and digits contralateral to the lesion), and orolingual (empty jaw movements andcontralateral tongue protrusion). A score from 0 to 4 was assigned
to each rat for each of the four subtypes on the basis of the proportion of the monitoring period during which the given behavior wasobserved.
The animals in all three groups were perfused on the 15th day.
Two hours after the ﬁnal injection, they were deeply anesthetizedwith an overdose of pentobarbital and perfused transcardially withsaline followed by 4% paraformaldehyde in 0.1-M phosphate buffer(PB; pH 7.4). Their brains were removed immediately and postﬁxed
at 4 ◦ C for 1 h in the above ﬁxative. After ﬁxation, the samples were
immersed at 4 ◦ C for 1 h in 0.1-M PB with 10% sucrose and then cryoprotected at 4 ◦ C overnight in the same buffer with 30% sucrose.
The samples were subsequently cut on a freezing microtome into
50-␮m coronal sections for immunohistochemistry. An immunohistochemical examination of FosB, c-Fos, or Zif268 expression
was performed, as described elsewhere [17]. The antibodies for
FosB (diluted 1:5000), c-Fos (1:5000), and Zif268 (1:3000) wererabbit polyclonal antisera (sc-48, sc-52, and sc-110, respectively;
Santa Cruz Biotechnology, CA, USA). The anti-pan-FosB antibody
was raised to the N-terminus of FosB and recognizes both FosB
and full-length FosB. FosB is a member of the Fos family of transcription factors, which dimerize with a member of the Jun family
and form activator protein-1 (AP-1) transcription factor complexes.
These complexes bind to AP-1 sites in the regulatory regions ofmany genes [21]. FosB is induced in the brain in response tochronic perturbations and lives much longer than other Fos-likeproteins (for example, c-Fos, FosB, Fra-1, Fra-2) induced acutely[9].
For each animal and each IEG protein, three sections throughthe Cg, AcbSh, and dorsolateral CPu approximately 1.2 mm rostral
to the bregma and three sections through the BLA approximately
2.3 mm caudal to the bregma were selected for quantitative analysis [23]. FosB, c-Fos, or Zif268 immunoreactivity in the Cg,
AcbSh, CPu, and BLA was quantiﬁed by counting the number ofcells immunopositive for FosB, c-Fos, or Zif268, respectively, in
0.25 mm × 0.25 mm (0.0625 mm2 ) squares using a 20× microscopeAuthor's personal copy
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K. Ebihara et al. / Neuroscience Letters 496 (2011) 90–94

Fig. 2. Photomicrographs of FosB (A–C), c-Fos (D–F), and Zif268 (G–I) expression in dorsolateral CPu ipsilateral to the 6-OHDA lesion for rats in saline (A, D, and G), acutel-DOPA (B, E, and H), and chronic l-DOPA (C, F, and I) treatment groups. Scale bar = 100 ␮m.

objective. The numbers obtained for the three sections in each area
(Cg, AcbSh, CPu, and BLA) were averaged to give the results for eachanimal and each IEG protein. The data are therefore presented as
the number of cells immunopositive for FosB, c-Fos, or Zif268 per
0.0625 mm2 of striatal or amygdalar tissue.
The behavioral data for the AIMs were analyzed nonparametrically using the Wilcoxon signed rank test. Two-way ANOVA withrepeated measures was used to statistically analyze the histological data followed by Bonferroni post hoc tests. P values < 0.05 wereregarded as being statistically signiﬁcant.
Of the eight rats that received chronic l-DOPA treatment, sixreached maximal dyskinesia severity (grade 4) in at least one of
the four AIM subtypes, and the other two reached grade 3 severity
in at least one subtype by the end of the treatment. As shown in
Fig. 1, the score for each subtype (locomotive, axial, forelimb, andorolingual) showed a signiﬁcant increase (about 7-, 4-, 22-, and 14fold, respectively) on the 14th day compared to on the 1st day of
l-DOPA administration.

In the saline-treated control animals, the number of FosBimmunopositive cells was signiﬁcantly greater in the dorsolateralCPu on the lesion side than on the intact side (Table 1), and thenumber of c-Fos- and Zif268-immunopositive cells was signiﬁcantly smaller in the Cg on the lesion side than on the intact side
(Tables 2 and 3). In the acute l-DOPA treated animals, the number of FosB-immunopositive cells was signiﬁcantly greater in the
AcbSh and CPu (Table 1), the number of c-Fos-immunopositive
cells was signiﬁcantly greater in the Cg, AcbSh, CPu, and BLA(Table 2), and the number of Zif268-immunopositive cells was signiﬁcantly greater in the AcbSh and CPu on the lesion side than in
the corresponding regions on the lesion side of the control animals (Table 3). In the chronic l-DOPA treated animals, the numberof FosB-immunopositive cells was signiﬁcantly greater in the Cg
and CPu on the lesion side than in the corresponding regions on
the lesion side of the acute l-DOPA treated animals (Table 1 andFig. 2), and the number of c-Fos-immunopositive cells was signiﬁcantly smaller in the Cg, AcbSh, and BLA on the lesion side

Table 1
Mean ± SEM of number of FosB-immunopositive cells/0.0625 mm2 .
Structure

Cg
AcbSh
CPu
BLA
*

Acute l-DOPA

SalineLesion side (n)Intact side (n)Lesion side (n)Intact side (n)Lesion side (n)Intact side (n)7.6 ± 1.2(8)37.3 ± 3.4(8)33 ± 6.2(8)6.0 ± 1.0(8)9.8 ± 1.8(8)30.8 ± 3.0(8)3.9 ± 0.6(8)$$7.7 ± 0.8(8)6.4 ± 0.4(7)62.5 ± 6.3(5)*76.9 ± 7.4(5)**5.9 ± 1.1(5)6.1 ± 0.6(7)36.4 ± 6.0(5)$3.8 ± 0.8(5)$$2.1 ± 0.9(5)13.5 ± 1.0(8)** , ‡78.2 ± 7.6(7)**102.1 ± 4.4(7)** , †17.2 ± 7.0(5)6.8 ± 1.4(8)$$34.4 ± 5.3(7)$$4.2 ± 1.0(7)$$10.6 ± 2.5(5)P < 0.05 vs. corresponding side of saline group.
P < 0.01 vs. corresponding side of saline group.
P < 0.05 vs. corresponding side of acute l-DOPA group.
‡P < 0.01 vs. corresponding side of acute l-DOPA group.
$P < 0.05 vs. lesion side of each structure/group.
$$P < 0.01 vs. lesion side of each structure/group.
**†

Chronic l-DOPAAuthor's personal copy
K. Ebihara et al. / Neuroscience Letters 496 (2011) 90–94

93

Table 2
Mean ± SEM of number of c-Fos-immunopositive cells/0.0625 mm2 .
Structure

Cg
AcbSh
CPu
BLA

Acute l-DOPA

SalineChronic l-DOPA

Lesion side (n)Intact side (n)Lesion side (n)Intact side (n)Lesion side (n)Intact side (n)8.7 ± 0.7(8)18.1 ± 2.6(8)2.9 ± 0.9(8)5.4 ± 1.2(8)16.2 ± 2.5(8)$$20 ± 2.1(8)3.5 ± 1.3(8)5.7 ± 0.9(8)28.1 ± 2.8(7)**102.3 ± 22.3(6)**86.2 ± 12.5(6)**24.7 ± 1.8(5)**20.8 ± 2.4(7)$$17.5 ± 3.6(6)$$8.4 ± 4.4(6)$$
14.6 ± 5.2(5)$$16.3 ± 2.3(8)* , ‡50.8 ± 5.1(9)** , †59.6 ± 9.3(9)**12.8 ± 1.3(7)* , ‡11.5 ± 1.3(8)$ , †15.8 ± 2.2(9)$$5.6 ± 0.8(9)$$10.7 ± 1.5(7)*P < 0.05 vs. corresponding side of saline group.
P < 0.01 vs. corresponding side of saline group.
†P < 0.05 vs. corresponding side of acute l-DOPA group.
‡P < 0.01 vs. corresponding side of acute l-DOPA group.
$P < 0.05 vs. lesion side of each structure/group.
$$P < 0.01 vs. lesion side of each structure/group.
**

Table 3
Mean ± SEM of number of Zif268-immunopositive cells/0.0625 mm2 .
Structure

Cg
AcbSh
CPu
BLA

Acute l-DOPA

SalineChronic l-DOPA

Lesion side (n)Intact side (n)Lesion side (n)Intact side (n)Lesion side (n)Intact side (n)36.5 ± 7.1(8)44.7 ± 5.7(8)54.2 ± 7.4(8)21.6 ± 3.9(8)50.1 ± 10.1(8)40.5 ± 4.9(8)55.4 ± 3.7(8)18.4 ± 2.7(8)53.2 ± 6.2(5)109.3 ± 13.3(5)**131 ± 10.6(5)**17.5 ± 3.6(5)43.6 ± 4.5(5)39.4 ± 6.9(5)$$80.5 ± 13.4(5)$$11.9 ± 4.8(5)28.6 ± 3.4(5)79.8 ± 10.1(6)103.9 ± 5.5(7)**16.0 ± 3.4(6)30.0 ± 3.3(5)46.3 ± 9.7(6)$$78.2 ± 7.4(7)$23.8 ± 8.6(6)$**

P < 0.01 vs. corresponding side of saline group.
P < 0.05 vs. lesion side of each structure/group.
$$P < 0.01 vs. lesion side of each structure/group.
$

than in the corresponding regions on the lesion side of the acutel-DOPA treated animals (Table 2). Statistical analysis of the number of FosB-immunopositive cells in the AcbSh showed that themain effects of group (saline, acute l-DOPA, chronic l-DOPA), of
laterality (lesion side, intact side), and of group × laterality weresigniﬁcant [group: F(2,19) = 35.0, P < 0.01; laterality: F(1,19) = 31.2,
P < 0.01; group × laterality: F(2,19) = 7.8, P < 0.01]. However, subsequent post-hoc Bonferroni tests showed no signiﬁcant difference
between the acute and chronic l-DOPA groups (P = 0.28) (Table 1).
A signiﬁcant difference was not found for the number of FosBimmunopositive cells in the BLA among the three groups andbetween the two sides [group: F(2,15) = 3.8, P = 0.05; laterality:
F(1,15) = 3.3, P = 0.09; group × laterality: F(2,15) = 2.6, P = 0.11].
In summary, comparison of the results of the acute and chronicl-DOPA treatment revealed that the chronic treatment resulted ina signiﬁcant upregulation of FosB in the Cg and CPu and in a signiﬁcant downregulation of c-Fos in the Cg, AcbSh, and BLA on thelesion side.
The results of this study show that chronic l-DOPA treatmentof 6-OHDA rats causes an increase in the number of FosBimmunopositive cells not only in the dorsolateral CPu but also in
the Cg on the lesion side. It also causes a decrease in the numberof c-Fos-immunopositive cells in the Cg, AcbSh, and BLA on thelesion side. These results are the ﬁrst to demonstrate that chronicl-DOPA treatment of 6-OHDA-lesioned rats can alter the FosB andc-Fos expressions in forebrain regions other than the CPu or nucleus
accumbens (Acb).
The FosB/FosB-like transcription factors in the striatum ofdyskinetic animals account for a pronounced increase in proteinDNA binding activities at both AP-1 enhancers and cyclic AMP
response elements [3]. These transcription factors have been implicated in the dyskinesia priming process by a study using antisense
oligonucleotides against fosB/fosB mRNA [2]. Similar to the ﬁndings of a previous study [11], this study found enhanced FosB
expression in the dorsolateral CPu on the lesion side of 6-OHDA
rats without l-DOPA treatment. This enhanced expression was
also found in the CPu and AcbSh of both acute- and chronictreated l-DOPA rats and in the Cg of the chronic l-DOPA treated
rats.

The BLA has been implicated in the response to affective stimuli
and in the process of conditioned reinforcement [12]. Furthermore,
the BLA has a substantial projection directly to the Acb [1] andindirectly via the dorsal prefrontal cortex including the Cg [19].
The Acb area is thought to be integral to the reinforcing actions ofdrugs of abuse and to drug-induced psychosis. Thus, the BLA may
be, at least in part, involved functionally in the mechanisms underlying l-DOPA-induced psychotic conditions. In agreement with aprevious study [10], c-Fos expression was found to be induced byl-DOPA administration in the BLA ipsilateral to the lesion, especially for the rats in the acute l-DOPA treatment group. Additional
ﬁndings, especially for FosB expression, were not observed in the
immunohistochemical study.
Numerous studies of patients with schizophrenia or druginduced psychosis have demonstrated functional or morphologicalalterations in the forebrain regions, including the Cg andAcb [13,18]. The Cg area is crucial for integrating cognitiveand emotional processes in support of goal-directed behavior[13,22]. Therefore, the results of this study’s immunohistochemical examination may be related to the pathogenesis of not
only motor complications but also psychotic conditions inducedby chronic l-DOPA treatment, implicated in schizophrenia andmethamphetamine- or other drug-induced psychosis. Clearly,
further work is needed to deﬁne the causal mechanisms of l-DOPArelated adverse events.
In conclusion, differential expression of FosB, c-Fos, and Zif268
was observed in four forebrain regions (Cg, AcbSh, CPu, and BLA)
during a course of chronic l-DOPA treatment of 6-OHDA-treatedhemiparkinsonian rats.
Acknowledgment
The authors thank Ms. Fumiko Tsuda for her excellent technicalassistance.
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